[P3-1~146] Poster Presentation 3

[P3-139] PMA Increased The Surface Expression of TRPV4 Is Dependent on The Activation Of Protein kinase C (PKC)

^○Hueng-Chuen Fan^{1, 2, 3} (1.Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, Taichung, 435, Taiwan, ROC, 2.Department of Medical Research, Tungs’ Taichung Metroharbor Hospital, Taichung, 435, Taiwan, ROC, 3.Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom)

TRPV4, a member of the vanilloid subfamily of the transient receptor potential channels, is activated by membrane stretch, by non-noxious warm temperatures, and by a range of chemical activators. TRPV4 is widely expressed in the kidneys, lungs, heart, brain and endothelial cells. The broad spectrum of activators and the wide distribution of TRPV4 suggest that the functions of TRPV4 extend beyond osmosensation. In the previous study, we showed PKC activation could sensitize TRPV4 to mechanical stimuli and identified the relevant phosphorylation sites, supporting the notion that TRPV4 functions as a nociceptor and the activation of PKC plays a vital role in the process of inflammatory hyperalgesia. In the present study, we found that PMA, a PKC activator, significantly increased the TRPV4 protein membrane expression. The increase was suppressed by prior exposure to by the PKC inhibitors staurosporine, bisindolylmaleimide I, rottlerin, and the cells expressing mutant TRPV4 constructs. Accordingly, PMA increased the surface expression of functional TRPV4 channels through activation of PKC. PKC inhibitors and TRPV4 mutant constructs internalized TRPV4 membrane proteins destined for lysosomal degradation through ubiquitinatination. Understanding the regulation of TRPV4 at the cell surface may provide an approach to the understanding of the neuropathic pain in patients with Charco-Marie Tooth (CMT) disease.